Macrophages are heterogeneous myeloid phagocytes that drive host defense and wound repair through unresolved mechanisms. This project investigates lung macrophage biology in the context of host immunity and tissue repair following parasitic helminth infection. More than one billion people worldwide are infected with parasitic helminthes and depending upon the worm species, infected individuals can suffer various degrees of lung injury. Historical data from chest x-ray images of worm-infected individuals revealed spontaneous resolution of tissue damage occurred following anti-helminthic therapy. Our data shows that lung macrophages are essential for the transient nature of helminth induced lung injury. This renewal application will establish the mechanism(s) used by lung macrophages to suppress pathogen-specific inflammation, facilitate re- epithelialization and restore lung gas exchange function. We will genetically deplete CD68+ tissue macrophages, monitor blood oxygen content (SpO2), and track both pro-inflammatory group 2 innate lymphoid cells (ILC2) and immunosuppressive regulatory T cell populations to achieve our project goals. We have evidence that lung macrophage depletion causes increased expansion of ILC2 and reduces interleukin 10 levels within injured lung tissue. Moreover, we provide evidence that macrophages drive re-epithelialization through producing Wnt proteins, which are established mediators of epithelial cell regeneration. Therefore, our project investigates mechanisms of host protective immunity during hookworm infection as a surrogate for understanding reversible lung injury. A clearer understanding of lung repair following infection is extremely important for millions of individuals suffering from acute and chronic forms of lung disease. Combined, acute and chronic lung diseases are predicted to be the 3rd leading cause of death within the United States by 2020. Clearly, there is a great need for understanding how inflammation and repair are regulated within the pulmonary tract. Therefore, we will test the hypothesis that lung macrophages produce immunosuppressive cytokines that limit ILC2 expansion and promote regulatory T cell expansion and also that lung macrophages directly promote epithelial regeneration via a Wnt4a-dependent mechanism. This hypothesis will be tested in the following specific aims: Aim 1 will determine whether repair of pulmonary function and restoration of lung homeostasis requires lung macrophages or ILC2. Aim 2 will determine whether lung macrophages suppress ILC2 or induce regulatory T cell expansion via IL-10 and/or TGF-? dependent mechanisms and Aim 3 will identify the molecular mechanism(s) responsible for macrophage-driven epithelial regeneration. Completion of this work will provide a deeper understanding of how infection-induced inflammation and pulmonary tissue regeneration are orchestrated via myeloid and lymphoid lineages.